A variety of inflammatory agents can provoke airflow limitation, including allergens, cold air, exercise, infections and air pollution. In particular, allergens and other agents in allergic or sensitized mammals (i.e., antigens and haptens) cause the release of inflammatory mediators that recruit cells involved in inflammation. Such cells include lymphocytes, eosinophils, mast cells, basophils, neutrophils, macrophages, monocytes, fibroblasts and platelets. A common consequence of inflammation is airway hyperresponsiveness (AHR). A variety of studies have linked the degree, severity and timing of the inflammatory process with the degree of airway hyperresponsiveness.
Airway hyperresponsiveness (AHR) is the result of complex pathophysiological changes in the airway. A variety of studies have linked the degree, severity and timing of the inflammatory process with the degree of airway hyperresponsiveness. However, the mechanisms leading to AHR are still poorly understood and can be attributed to both immune-dependent and immune-independent mechanisms. Essentially all of the T cell-mediated effects described so far are in the former category. However, T cells from hyperresponsive mice can increase baseline airway tone in hyporesponsive mice after cell transfer.
Currently, therapy for treatment of inflammatory diseases involving AHR, such as moderate to severe asthma and chronic obstructive pulmonary disease, predominantly involves the use of glucocorticosteroids and other anti-inflammatory agents. These agents, however, have the potential of serious side effect, including, but not limited to, increased susceptibility to infection, liver toxicity, drug-induced lung disease, and bone marrow suppression. Thus, such drugs are limited in their clinical use for the treatment of lung diseases associated with airway hyperresponsiveness. The use of anti-inflammatory and symptomatic relief reagents is a serious problem because of their side effects or their failure to attack the underlying cause of an inflammatory response. There is a continuing requirement for less harmful and more effective reagents for treating inflammation. Thus, there remains a need for processes using reagents with lower side effect profiles, less toxicity and more specificity for the underlying cause of AHR.
Airway hyperresponsiveness in asthma and other conditions associated with allergic inflammation increases after exposure to allergen. The level of responsiveness can be demonstrated by showing increased responses to bronchoconstrictors such as methacholine (MCh). This heightened responsiveness is thought to result from a complex inflammatory cascade involving several cell types, including T lymphocytes and eosinophils (Gelfand & Irvin, (1997) Nat. Med. 3, 382-384; Wills-Karp, (1999) Ann. Rev. Immunol. 17, 255-281). T lymphocytes exert many of their effects by secreting an array of cytokines. More specifically, the present inventors and others have previously shown that αβ T cells are necessary for the development of allergic inflammation and airway hyperresponsiveness (AHR) (e.g., (Hamelmann et al., (1996) J. Exp. Med. 183:1719-1729; Holt, (1996) J. Exp. Med. 183:1297-1301; Takeda et al. (1997) J. Exp. Med. 186:449-454; and Lahnet al., (1999) Nature Med. 5:1150-6). In addition, it has been shown that in a model of acute allergic inflammation TCR-β−/− mice do not develop eosinophilia in the BAL fluid and in the lung tissue and do not develop AHR. (Lahn et al., (1999) ibid.) and similar results were shown in a chronic model of allergic inflammation (Seymour et al. (1998) J. Exp. Med. 187:721-731).
In recent years humanized monoclonal antibodies (mAb) have become an attractive pharmacological treatment option in patients suffering from different diseases (See, e.g., Table 1). Several publications and patents describe antibodies against various receptors on T cells, including the T cell antigen receptor (TCR), CD3, and CD4. For example, U.S. Pat. Nos. 4,658,019 and 6,113,901 describe antibodies against the CD3 complex and the use of such antibodies in the suppression of the immune system ('019), or the induction of passive immunity ('901). U.S. Pat. Nos. 5,223,426 and 6,171,799 describe antibodies against the TCR α or β chains and the use of such antibodies to treat conditions and disorders of the immune system by stimulation or suppression of T cells. Among the application of mAbs as immunotherapeutics, the use of mAbs against CD3 complex, CD4 and IL-2R have been studied in different clinical trials (Yocum, Seminars in Arthritis and Rheumatism 29:27-35 (1999); Offner et al., Springer Seminars in Immunopathology 21:77-90 (1999)). In lung related diseases, however, only mABS against CD4 and IgE have been used in patients with asthma (Kon et al., Lancet 352:1109-13 (1998); Kon et al., Inflammation Research 48:516-23 (1999); Milgrom et al., N Engl J Med 341:1966-73 (1999)). In both these therapeutic approaches, mAbs were applied intravenously.
TABLE 1Currently Available Monoclonal Antibodies for Clinical ApplicationNameActionDrug Name (Company)IndicationAdministration (Adults)PalivizumabIgG1k against A antigenic site ofSynagis (Medlmmune)RSV in children15 mg/kg i.m.the F protein of RSVBasiliximabIgG1K against IL-2Rα (CD25)Simulect (Novartis)Organ rejection, Prophylaxis20 mg each (2 doses)DaclizumabIgG1 against α-subunit (TacZenapax (Roche)Organ rejection, Prophylaxis1 mg/kg i.v. (5 doses)subunit) of IL-2RMuromonab-CD3IgG2a against T3 (CD3)Orthoclone OKT3 (Ortho Biotech)Organ rejection5 mg/day for 10-14 daysas i.v. bolusEtanerceptDimeric fusion protein consistingEnbrel (Immunex)Rheumatoid Arthritis25 mg twice weekly s.c.of the extracellular ligand-bindingportion of TNF-Rp75RituximabIgG1K against CD20Rituxan (IDEC/Genentech)CD20+ Non-Hodgkin’s375 mg/m2 asLymphomai.v. infusiononce weekly for 4 dosesAbiciximabMAb against glycoprotein-IIb/IIIa-ThrombembolusR on platlets (clone c7E3 Fab)TrastuzumabMAb against extracellular domainHerceptin (Genentech)HER2 overexpressing BreastInitially, 4 mg/kg over 90of hEGF-R2 protein (HER2)Cancermin, then 2 mg/kgover 30 min weeklyEdrecolomabMAb (clone 17-1A) against colonPanorex (?)Adjuvant therapy in colon500 mg i.v., thentumor antigen 17-1Acancermonthly 100 mgKeliximabMAb against CD4(SmithKline Beecham)RA, MS, IBD, Skin disordors,0.5-1.5 mg/kg i.v.asthmahuMAb-E25Mab against IgE(Genentech)Asthmai.v.Mab PM-81 and(Medarex)Exogenous depletion ofExperimental ?AML-2-23CD14+ andCD15+ AML bone marrow cellsfrom patients undergoingbone marrowtransplantationMAb for(VivoRx Autoimmune)Lupus nephritisExperimental ?immunizationagainst lupusnephritisMAb PM-81(Medarex)Adjunctive treatment for AMLExperimental ?MAb to CD22LymphoCIDE (Immunomedics)NHLExperimental ?(radiolabelled)MAb to CMV(Protein Design Labs)CMV retinitis in AIDSExperimental ?MAb to h-HBV(Protein Design Labs)Prophylaxis of Hepatitis BExperimental ?reinfection inliver transplantationMAb B43.13OVArex Mab-B43.13 (AltaRex)Epithelial Ovarian CancerExperimental ?NebacumabIgM (clone HA-1A) binds to LipidCentoxin (Centocor)Gram-negative bacterimiaExperimental; withdrawnAprogressed to septic shockfrom European Market:100 mg i.v. over 30 minEdobacomabIgM (clone ES) against coreGram-negative bacterimia onlyExperimental ?glycolipidMAb MSL-109antiviral(Sandoz)AIDSExperimental, Phase IMab 5c8(Biogen)Immune ThrombocytopenicExperimental ?purpura, SLE
Recently, there has been some interest in delivery mechanisms for therapeutic antibodies. One area of interest is in the delivery of therapeutic antibodies by pulmonary delivery. For example, U.S. Pat. No. 6,165,463 to Inhale Therapeutic Systems, Inc. describes a dispersible dry powder that can be used for the pulmonary delivery of antibodies. The '463 patent references several different therapeutic antibodies that are currently being evaluated for use in the treatment of various conditions, including various viral infections, cancer, bacterial infections, allergic reactions and other inflammatory conditions, particularly those that affect the pulmonary tissues.
However, in practice, at least with regard to airway responses in the lung, attempts to use aerosolized therapeutic antibodies have not generally met with success. For example, Fahy et al. used aerosolized anti-IgE to test whether direct delivery of the antibody to the airway would have the same effect as the systemic delivery of the antibody, which attenuated early and late phase responses to inhaled allergen (Fahy et al., 1999, Am. J. Respir. Crit. Care Med. 160:1023-1027). It was shown that the aerosolized anti-IgE did not inhibit the airway responses to inhaled allergen and in at least one subject, the antibody proved to be immunogenic. Fahy et al. concluded that the observed lack of efficacy was probably due to the inability of the aerosol route of delivery to result in high enough concentrations of antibody in the lung tissue compartments to neutralize IgE. Indeed, U.S. Pat. No. 6,165,463, described above, indicates that antibodies are considered to be “low potency” drugs, and therefore indicates that fairly high concentrations of antibodies (e.g., in the milligram per milliliter range) should be formulated for aerosol delivery.